rs199959895

Variant names:

• chr18-62074818-A-T
• rs199959895
• NM_176787.5:c.2580T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_176787.5(PIGN):​c.2580T>A​(p.Leu860Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,605,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: PIGN NM_176787.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.49
• Publications: 1 publications found

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Fryns syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 18-62074818-A-T is Benign according to our data. Variant chr18-62074818-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176787.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	NM_176787.5	MANE Select	c.2580T>A	p.Leu860Leu	synonymous	Exon 29 of 31	NP_789744.1	O95427
	PIGN	NM_001438896.1		c.2580T>A	p.Leu860Leu	synonymous	Exon 29 of 32	NP_001425825.1
	PIGN	NM_012327.6		c.2580T>A	p.Leu860Leu	synonymous	Exon 28 of 30	NP_036459.1	O95427

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGN	ENST00000640252.2	TSL:1 MANE Select	c.2580T>A	p.Leu860Leu	synonymous	Exon 29 of 31	ENSP00000492233.1	O95427
	PIGN	ENST00000400334.7	TSL:1	c.2580T>A	p.Leu860Leu	synonymous	Exon 28 of 30	ENSP00000383188.2	O95427
	PIGN	ENST00000638424.1	TSL:5	n.*548T>A		non_coding_transcript_exon	Exon 27 of 29	ENSP00000491963.1	A0A1W2PQZ1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000181 AC: 44 AN: 243524 AF XY: 0.000197

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.000673

GnomAD4 exome AF: 0.000267 AC: 388 AN: 1452890 Hom.: 0 Cov.: 26 AF XY: 0.000268 AC XY: 194 AN XY: 723006

African (AFR) AF: 0.0000601 AC: 2 AN: 33284

American (AMR) AF: 0.0000676 AC: 3 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 85220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000329 AC: 364 AN: 1105504

Other (OTH) AF: 0.000316 AC: 19 AN: 60090

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74382

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000200

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.4
DANN	Benign	0.63
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199959895; hg19: chr18-59742051;